title: Influence of chlorine substitution on the hydrolytic stability of biaryl ether nucleoside adducts produced by phenolic toxins.
abstract: A kinetic study is reported for the acid-catalyzed hydrolysis of oxygen (O)-linked biaryl ether 8-2'-deoxyguanosine (dG) adducts produced by phenolic toxins following metabolism into phenoxyl radical intermediates. Strikingly, the reaction rate of hydrolysis at pH 1 decreases as electron-withdrawing chlorine (Cl) substituents are added to the phenoxyl ring. The Hammett plot for hydrolysis at pH 1 shows a linear negative slope with ρX = -0.65, implying that increased Cl-substitution diminishes the rate of hydrolysis by lowering N(7) basicity. Spectrophotometric titration provided an N(7)H(+) pKa value of 1.1 for the unsubstituted adduct 8-phenoxy-dG (Ph-O-dG). Model pyridine compounds suggest N(7)H(+) pKa values of 0.92 and 0.37 for 4-Cl-Ph-O-dG and 2,6-dichloro-Ph-O-dG (DCP-O-dG), respectively. Density functional theory (DFT) calculations also highlight the ability of the 8-phenoxy substituent to lower N(7) basicity and predict a preference for N(3)-protonation for highly chlorinated O-linked 8-dG adducts in water. The calculations also provide a rationale for the hydrolytic reactivity of O-linked 8-dG adducts in the gas-phase, as determined using electrospray mass spectrometry (ESI-MS). The inclusion of our data now establishes that the order of hydrolytic reactivity at neutral pH for bulky 8-dG adducts is N-linked > C-linked > O-linked, which correlates with their relative ease of N(7)-protonation.
authors.affiliation: Department of Chemistry, University of Guelph, Guelph, Ontario, N1G 2W1, Canada.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kuska
authors.forename: Mohadeseh
authors.initials: M
authors.lastname: Majdi Yazdi
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Witham
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Dahlmann
authors.forename: Shana J
authors.initials: SJ
authors.lastname: Sturla
authors.forename: Stacey D
authors.initials: SD
authors.lastname: Wetmore
authors.forename: Richard A
authors.initials: RA
authors.lastname: Manderville
mesh_terms: D000143:Acids / Q000737:chemistry; D002384:Catalysis; D002713:Chlorine / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D004987:Ethers / Q000138:chemical synthesis* / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D019800:Phenol / Q000737:chemistry*; D011789:Quantum Theory
chemical_list: D000143:Acids; D004987:Ethers; D019800:Phenol; D002713:Chlorine; D003849:Deoxyguanosine